ABSTRACT The long range objective of our laboratory is to understand the cellular and molecular mechanisms by which signaling pathways and downstream transcription factors coordinate the specification of adrenocortical cells within the adrenal gland. Our goal during this grant cycle is to define the mechanisms by which the Shh- expressing progenitor cells are maintained during adrenal homeostasis. Based on our preliminary data, we hypothesize that the adrenocortical progenitor pool is maintained through a coordinated balance of both 1) the proliferative self-renewal of the undifferentiated Shh-expressing cells and 2) the differentiation of the Shh- expressing progenitor to the distinct steroidogenic cell types in adrenal cortex. To this end our strategy and specific aims for this proposal are designed to define 1) the intracellular mechanisms by which steroidogenic factor 1 (SF1) is activated during cell cycle to initiate unique transcriptional programs in the proliferating undifferentiated Shh-expressing progenitor cell, and 2) how extracellular signals, specifically the balance of paracrine (SHH/WNT4) and endocrine (circulating Angiotensin II) factors regulates progenitor cell fate under physiological conditions. The studies proposed here will provide fundamental knowledge of adrenal homeostatic maintenance and will provide the groundwork for future clinical insights and novel therapeutic treatments for patients with intrinsic or iatrogenic adrenal failure.